WO2009154276A1 - Cristaux de dérivé de spirocétal et leur procédé de fabrication - Google Patents

Cristaux de dérivé de spirocétal et leur procédé de fabrication Download PDF

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WO2009154276A1
WO2009154276A1 PCT/JP2009/061226 JP2009061226W WO2009154276A1 WO 2009154276 A1 WO2009154276 A1 WO 2009154276A1 JP 2009061226 W JP2009061226 W JP 2009061226W WO 2009154276 A1 WO2009154276 A1 WO 2009154276A1
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formula
compound
alkyl
crystal
aryl
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PCT/JP2009/061226
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English (en)
Japanese (ja)
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政利 村形
拓真 池田
伸彰 木村
朗 川瀬
正弘 永瀬
山本　啓介
則幸 高田
慎一 吉崎
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中外製薬株式会社
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Priority to US13/000,208 priority Critical patent/US8569520B2/en
Priority to MX2010014023A priority patent/MX2010014023A/es
Priority to CA2727923A priority patent/CA2727923A1/fr
Priority to EP22155547.7A priority patent/EP4036100A1/fr
Priority to CN200980119081.4A priority patent/CN102046645B/zh
Priority to PL16202285T priority patent/PL3170834T3/pl
Priority to JP2010517979A priority patent/JP4823385B2/ja
Priority to NZ589961A priority patent/NZ589961A/xx
Priority to EP16202285.9A priority patent/EP3170834B8/fr
Priority to EP09766724.0A priority patent/EP2308886B1/fr
Priority to AU2009261129A priority patent/AU2009261129A1/en
Priority to KR1020117000778A priority patent/KR101856784B1/ko
Application filed by 中外製薬株式会社 filed Critical 中外製薬株式会社
Publication of WO2009154276A1 publication Critical patent/WO2009154276A1/fr
Priority to IL210098A priority patent/IL210098A0/en
Priority to MA33442A priority patent/MA32530B1/fr
Priority to ZA2011/00016A priority patent/ZA201100016B/en
Priority to HK11108698.5A priority patent/HK1154589A1/xx
Priority to US14/034,880 priority patent/US9163051B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Definitions

  • the present invention relates to a process for the preparation of spiroketal derivatives, synthetic intermediates useful for the preparation of spiroketal derivatives, and crystalline substances of spiroketal derivatives.
  • Patent Document 1 WO2006 / 080421A1
  • Patent Document 1 discloses a method for producing a compound represented by Formula (A), and in Scheme 3 (Patent Document 1, page 24), after making a dibromobenzene derivative react with an alkyllithium reagent, The method of coupling with a lactone and further converting into a tin compound, followed by a coupling reaction in the presence of a palladium catalyst to obtain a target compound is described.
  • a dihalotoluene derivative is n-BuLi. After treatment with s-BuLi, t-BuLi or Mg, etc., coupled with a lactone, and after several steps, converted to a tin compound and coupled with a benzyl halide derivative to obtain a target compound Is described.
  • An object of the present invention is to provide an efficient and convenient method for industrially producing spiroketal derivatives used as an active ingredient of pharmaceuticals, and to provide useful synthetic intermediates, and storage stability as pharmaceuticals or pharmaceutical raw materials It is an object of the present invention to provide a crystal having excellent properties in terms of properties, ease of handling at the time of preparation and the like.
  • the present inventors have found a method for regioselectively halogen-exchanging one of a plurality of halogen atoms on a benzene ring.
  • the coupling reaction proceeds smoothly by passing through a novel organometallic compound which is easy to prepare as an intermediate, and according to this method, two successive coupling reactions are efficiently performed as a one-pot reaction. It is found that the present invention is possible.
  • the present invention provides a method for producing a target spiroketal derivative without using heavy metals such as tin and organic transition metal complexes in carrying out carbon-carbon bond formation.
  • the method using heavy metals such as tin and organic transition metal complexes requires a step of carefully removing the reagent that may contaminate as an impurity, whereas the production method does not require such a step. It is particularly excellent as an industrial process for producing pharmaceutical raw materials.
  • the present inventors have found that the crystal form of the compound represented by the formula (I) and the process for producing the same, and that the crystal has excellent properties as a medicine or pharmaceutical raw material, and completed the present invention.
  • X 1 and X 2 are each independently selected from a bromine atom and an iodine atom; P 1 is a metal ion, a hydrogen atom or a hydroxy protecting group; R 41 is a group already defined as R 1 , provided that the group may have one or more protecting groups; n is as already defined. Is treated with an organometallic reagent, and then the compound of formula (III):
  • P 2 , P 3 , P 4 and P 5 are each independently selected from hydroxy protecting groups; or P 2 and P 3 , P 3 and P 4 , and P 4 and P 4 5 may be a divalent group which together form a ring by independently protecting each two hydroxy groups.
  • R 41 , n, X 2 , P 1 , P 2 , P 3 , P 4 and P 5 are as defined above;
  • P 6 is a metal ion, a hydrogen atom or a protecting group of a hydroxy group
  • R 42 is a group already defined as R 2 , provided that the group may have one or more protecting groups, and m is as defined above] Reacting with the compound of And the step of introducing a protecting group, and / or removing the protecting group at any step during and / or before and / or after the above process is provided. .
  • the method comprises Process c) Formula (VI):
  • halogen atom as used herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • C 1-10 alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl and s- Butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, cyclopropylmethyl, cyclohexylmethyl and the like.
  • C 1-10 alkyl further includes linear or branched C 1-6 alkyl, and C 1-4 alkyl.
  • C 3-10 cycloalkyl means a cyclic alkyl group having 3 to 10 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl and the like.
  • C 3-10 cycloalkyl further includes C 3-8 cycloalkyl and C 3-7 cycloalkyl.
  • C 2-10 alkenyl means a linear or branched alkenyl group having 2 to 10 carbon atoms, and examples thereof include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl) and propene-2 -Yl, 3-butenyl (homoallyl), 1,4-pentadien-3-yl and the like.
  • C 2-10 alkenyl further includes linear or branched C 2-6 alkenyl, and C 2-4 alkenyl.
  • C 3-10 cycloalkenyl means a cyclic alkenyl group having 3 to 10 carbon atoms, and examples include cyclopentenyl, cyclohexenyl and the like, and C 5-10 cycloalkenyl and the like.
  • C 2-10 alkynyl means a linear or branched alkynyl group having 2 to 10 carbon atoms, and includes, for example, ethynyl, 1-propynyl, 2-propynyl and the like.
  • C 2-10 alkynyl further includes linear or branched C 2-6 alkynyl, and C 2-4 alkynyl.
  • C 1-10 alkoxy refers to an alkyloxy group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and examples thereof include methoxy, ethoxy, n-propoxy and i-propoxy , N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methyl pen Toxy, 3-methyl pentoxy, 2-methyl pentoxy, 1-methyl pentoxy, 3-ethyl butoxy, 2-ethyl butoxy and the like.
  • C 1-10 alkoxy further includes linear or branched C 1-6 alkoxy, and C 1-4 alkoxy.
  • C 1-10 alkylamino means an alkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and examples thereof include methylamino, ethylamino and n-propylamino. And i-propylamino, n-butylamino, s-butylamino, i-butylamino, t-butylamino and the like.
  • C 1-10 alkylamino further includes linear or branched C 1-6 alkylamino, and C 1-4 alkylamino.
  • di (C 1-10 alkyl) amino means a dialkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and the alkyl moieties may be the same.
  • Di (C 1-10 alkyl) amino further includes linear or branched di (C 1-6 alkyl) amino, and di (C 1-4 alkyl) amino.
  • C 1-10 alkylthio means an alkylthio group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and examples thereof include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-butylthio and the like are included.
  • C 1-10 alkylthio further includes linear or branched C 1-6 alkylthio, and C 1-4 alkylthio.
  • saturated, partially unsaturated or unsaturated heterocyclyl as used herein is, for example, saturated, partially unsaturated, comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. Or unsaturated 4 to 10 membered heterocyclic group is meant.
  • heterocyclyl examples include pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperidyl, homopiperazinyl and morpholinyl and the like.
  • aryl is not particularly limited, but means an aryl group having an aromatic hydrocarbon ring having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, and examples thereof include phenyl, 1-naphthyl and 2-naphthyl. And so on.
  • heteroaryl means a 4- to 10-membered aromatic heterocyclic group, including but not limited to, for example, one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms.
  • heteroaryl include pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and the like.
  • carrier as used herein is not particularly limited, but means a hydrocarbon ring having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, and includes, for example, benzene, naphthalene and the like.
  • heterocycle means a 4- to 10-membered heterocycle, including but not limited to, for example, one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. Do.
  • heterocycles include pyridine, pyrimidine, pyrazine, triazine, quinoline, quinoxaline, quinazoline, furan, thiophene, pyrrole, pyrazole, imidazole, and triazole.
  • the group defined as R 1 and R 2 has one or more protectable groups such as hydroxy, carboxy, carbonyl, amino, mercapto and the like, the group is protected by a protecting group It is also good.
  • the selection of the protective group introduced into each group and the desorption operation can be carried out, for example, based on the description of "Greene and Wuts,” Protective Groups in Organic Synthesis “(4th Edition, John Wiley & Sons 2006)". .
  • R 51 is each independently aryl optionally substituted by one or more R 56, C 1-10 alkoxy optionally substituted by one or more aryl, C 1-10 alkylthio, and aryl Selected from serenyl;
  • R 52 is independently selected from C 1-10 alkoxy;
  • R 53 and R 55 are each independently selected from C 1-10 alkyl and aryl;
  • R 54 is a hydrogen atom, C 1-10 alkyl, aryl optionally substituted by one or more C 1-10 alkoxy, heteroaryl, amino optionally substitute
  • Preferred examples of the hydroxy protecting group include methyl, benzyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiophenyl and 1-ethoxyethyl.
  • the protecting group of the amino group which may be contained in R 1 and / or R 2 , C 1-10 alkyl optionally substituted by one or more R 51 , even substituted by one or more R 52 Good saturated, partially unsaturated or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , —C (OO) R 54 and the like, wherein R 51 to R 54 are already As defined.
  • R 51 to R 54 are already As defined.
  • benzyl etc. are mentioned, Moreover, a primary amino group can also be converted and protected to a phthalimido group and a succinimide group.
  • Examples of the protecting group of the carboxy group which may be contained in R 1 and / or R 2 include C 1-10 alkyl optionally substituted by one or more R 51 , C 2-10 alkenyl, -Si (R 53 An ester-forming group such as 3 (where R 51 and R 53 are as previously defined), or an amide-forming group such as -NR 58 R 59 (where R 58 and R 59 are each independently , C 1-10 alkyl optionally substituted by one or more R 51 , C 2-10 alkenyl, -Si (R 53 ) 3 , wherein R 51 and R 53 are as defined above A) etc.
  • Preferred examples of the conversion of carboxy by the introduction of a protecting group include ethyl ester, benzyl ester, t-butyl ester and the like.
  • Groups formed by introducing one or more protecting groups into groups defined as R 1 and R 2 are included in the definition of R 41 and R 42 .
  • R 1 and R 2 defined in the present invention are not particularly limited, but for example, each is independently substituted by C 1-10 alkyl optionally substituted by one or more of Ra, one or more of Ra Optionally C 3-10 cycloalkyl, C 2-10 alkenyl optionally substituted by one or more Ra, C 3-10 cycloalkenyl optionally substituted by one or more Ra, one or more Ra C 2-10 alkynyl which may be substituted, aryl which may be substituted by one or more Ras, saturated, partially unsaturated or unsaturated heterocyclyl which may be substituted by one or more Ras, and -Selected from SiR 12 R 13 R 14 More preferably, R 1 and R 2 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, aryl, and —SiR 12 R 13 R 14 . In the present invention, when n or m is 0, R 1 or R 2 is not present on the benzene ring respectively. In one aspect of the invention, n
  • the halogen atom defined as R 1 and R 2 is preferably a fluorine atom or a chlorine atom.
  • the metal ion defined in P 1 , P 6 and X means a metal ion which is a counter ion of alkoxide ion, and, for example, an alkali metal such as lithium ion, sodium ion, potassium ion, cesium ion, magnesium ion Ions, alkaline earth metal ions, etc. may be mentioned, and they may form complexes with other metals.
  • the metal ions also include, for example, metal ions (eg, lithium ions) generated by causing an organometallic reagent used in the present invention to act on a hydroxy group.
  • the “hydroxy protecting group” included in the definition of P 1 to P 6 is not particularly limited as long as it is a group generally used as a hydroxy protecting group.
  • the selection of the protective group to be introduced into the hydroxy group and the introduction operation can be carried out, for example, based on the description of "Greene and Wuts,” Protective Groups in Organic Synthesis “(4th Edition, John Wiley & Sons 2006) .
  • a divalent group that protects two hydroxy groups to form a ring is a divalent group that links the oxygen atoms of the two hydroxy groups, eg, C 1-10 alkylene.
  • a group eg, methylene, methyl methylene, dimethyl methylene and the like
  • a carbonyl group and the like are meant.
  • the organometallic reagent used in the present invention is not particularly limited as long as it is an organometallic reagent suitable for performing a halogen transmetallation reaction on a benzene ring, and examples thereof include C 1-10 alkyllithium (eg, n-butyl) Lithium, s-butyllithium, t-butyllithium etc., aryllithium (eg phenyllithium, naphthyllithium, dimethoxyphenyllithium etc.), C 1-10 alkyl magnesium halide (eg n-butylmagnesium chloride, isopropylmagnesium chloride Etc.), di (C 1-10 alkyl) magnesium (eg, di (n-butyl) magnesium etc.) and the like.
  • C 1-10 alkyllithium eg, n-butyl
  • aryllithium eg phenyllithium, naphthyllithium, dimethoxypheny
  • the organometallic reagent is used in the presence of an inorganic salt or an organic salt (eg, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium triflate, magnesium chloride, magnesium bromide, magnesium triflate, etc.) It may also be used as a mixture with inorganic or organic salts.
  • an inorganic salt or an organic salt eg, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium triflate, magnesium chloride, magnesium bromide, magnesium triflate, etc.
  • examples of the organometallic reagent include a mixture or reaction product of a magnesium compound and an organic lithium compound described in, for example, pages 11 to 17 of WO 2001/057046, for example, butyl magnesium chloride and butyl lithium, isopropyl magnesium Bromide and butyllithium, isopropylmagnesium bromide and lithium chloride, dibutylmagnesium and butyllithium, dibutylmagnesium and ethoxylithium, dibutylmagnesium and t-butoxylithium, dibutylmagnesium and lithium hexamethyldisilazide, butylmagnesium bromide and butyllithium, isopropyl Magnesium bromide and butyllithium and lithium chloride, butylmagnesium chloride and butyllithium and ethoxylithium, A mixture or reaction product of magnesium chloride and butyl lithium and lithium hexamethyl disilazide, isopropyl
  • n-butyllithium is used as the organometallic reagent.
  • the organometallic reagent may be used by sequentially reacting two or more kinds of reagents to form a metal complex. For example, after treating a compound represented by formula (II) with butyllithium, butylmagnesium chloride and butyllithium may be added to the system and then reacted with a compound represented by formula (III).
  • the substituted silyl group specified by the formula -SiR 12 R 13 R 14 , the formula -SiR 23 R 24 R 25 , and the formula -Si (R 53 ) 3 in the present specification is not particularly limited. Triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl and the like.
  • X 1 and X 2 are, for example, both bromine atoms.
  • P 1 include, for example, lithium ion, hydrogen atom, and, for example, C 1-6 alkoxyC 1-6 alkyl (eg, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-l) Methylethyl etc., arylmethyloxy C 1-6 alkyl (eg benzyloxymethyl etc.) tetrahydropyranyl, group -Si (R 53 ) 3 (eg trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethyl Examples include protecting groups such as silyl, t-butyldiphenylsilyl and the like), aralkyl (eg, benzyl, 4-methoxybenzyl, trityl and the like),
  • the treatment of the compound of formula (II) with the organometallic reagent in step a) can be carried out using a solvent suitable for a halogen transmetallation reaction.
  • the solvent include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane and the like), hydrocarbons (for example, And pentane, hexane, heptane, benzene, toluene and the like), N, N-tetramethylethylenediamine, N, N-tetramethylpropanediamine, and a mixed solvent containing two or more of the above-mentioned solvents.
  • ethers for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether,
  • the organometallic reagent is 0.5 to 1.5 equivalents, for example, 0.8 to 1.1 equivalents, and when P 1 is a hydrogen atom, an organometallic reagent May use 1.5 to 3.0 equivalents, for example 1.8 to 2.2 equivalents.
  • the organic metal reagent may be added little by little, for example, by dropping over 15 minutes or more, preferably 15 to 300 minutes, more preferably 30 to 300 minutes. You may add. Also, the addition of the organometallic reagent may be performed intermittently.
  • the above addition time may include one or more interruption times, for example, two or three additions across one or two interruption times (eg, 5 to 300 minutes, preferably 15 to 120 minutes) It may be divided into
  • a predetermined amount for example, 0.05 to 0.5 equivalents, preferably relative to the amount of the reaction substrate contained in the reaction mixture from the beginning (0.1 to 0.4 equivalents) of an aryl halide may be added to the reaction mixture.
  • an aryl halide for example, iodobenzene, diiodotoluene, dibromotoluene, and a reaction substrate (eg, 2,4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene etc.), preferably a reaction substrate Can be used.
  • the organometallic reagent is, for example, added little by little (for example, dropwise Can be added.
  • the reaction may be completed by stirring at an appropriate temperature, for example, -80 to 0 ° C, preferably -15 to 0 ° C, for a certain time (for example, 0.1 to 5 hours) .
  • the organometallic reagent is added in an amount of less than 1 equivalent, for example 0.4 to 0.9 equivalent, preferably 0.8 equivalent.
  • a suitable temperature for example, -80 to 30 ° C, preferably -60 to 25 ° C, especially -15 to 0 ° C, for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2
  • the reaction mixture may be stirred for a period of time, and then an additional organometallic reagent is added, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, for example, -80 to 30 ° C., preferably -60 to
  • the reaction mixture may be stirred at 25 ° C., in particular at ⁇ 15 to 0 ° C., for a certain time, for example 0.1 to 5 hours, preferably 0.5 to 2 hours.
  • the number of equivalents represents a molar equivalent to the compound of the formula (II) which is a reaction substrate.
  • "equivalent” means molar equivalent unless otherwise stated.
  • the organometallic reagent is suitably added by adding less than 2 equivalents, for example 1.4 to 1.9 equivalents, preferably 1.8 equivalents.
  • the reaction is carried out at a temperature, for example, -80 to 30 ° C, preferably -60 to 25 ° C, particularly -15 to 0 ° C, for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours.
  • the mixture may be stirred, and then an additional organometallic reagent is added, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, for example, -80 to 30 ° C, preferably -60 to 25 ° C,
  • the reaction mixture may be stirred at ⁇ 15 to 0 ° C. for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours.
  • the number of equivalents represents a molar equivalent to the compound of the formula (II) which is a reaction substrate.
  • a halogen transmetalation reaction occurs preferentially in X 1 of the compound of the formula (II) having a plurality of reaction points, and as a result, byproducts derived from the halogen transmetalation reaction in X 2 This gives a greater amount of the desired compound of formula (IVa).
  • the reaction is a regioselective reaction.
  • the regioselectivity in step a) is not particularly limited, for example, the ratio of target product: byproduct is 10: 1 or more, preferably 30: 1 or more.
  • C 1-10 alkyllithium eg, n-butyllithium, s-butyllithium or t-butyllithium etc.
  • aryllithium eg, phenyllithium, naphthyllithium, dimethoxyphenyllithium etc.
  • another type of organometallic reagent such as n-butylmagnesium chloride and n-butyllithium or dibutylmagnesium
  • the complex may be formed after stirring the reaction mixture at -60 to 25 ° C., particularly at -15 to 0 ° C., for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours .
  • step a compounds of formula (II) are used in step a), wherein P 1 is a hydrogen atom.
  • examples of P 2 , P 3 , P 4 and P 5 include, for example, C 1-6 alkoxy C 1-6 alkyl (eg, methoxymethyl, ethoxymethyl 1-methoxyethyl, 1-methoxy-1-methylethyl, etc., arylmethyloxy C 1-6 alkyl (eg, benzyloxymethyl etc.), tetrahydropyranyl, group -Si (R 53 ) 3 (eg, trimethylsilyl) , Triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl etc., aralkyl (eg benzyl, 4-methoxybenzyl, triphenylmethyl etc.), group -B (OR 55 ) 2 , C 1 -6 alkyl carbonyl (eg, acetyl, propion
  • P 4 and P 5 are combined to protect two hydroxy groups to form a ring (eg, —CH 2 —, —CH (CH 3 ) —, —C (CH 3) 2 )-, -CHPh-, etc. may be used.
  • Reaction of a compound of formula (II) treated with an organometallic reagent with a compound of formula (III) can be carried out, for example, by reacting a solution of the compound of formula (II) in a suitable solvent at a suitable temperature, for example Into a reaction mixture containing a compound of formula (III) (for example 1.0 to 1.1 equivalents) at a temperature of -0 ° C, preferably -90 to -30 ° C, especially -80 to -40 ° C (Dropwise) can be added.
  • a compound of formula (III) for example 1.0 to 1.1 equivalents
  • Suitable solvents include, for example, ethers (eg, tetrahydrofuran (THF), methyl tetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane etc.), hydrocarbons And the like (eg, hexane, heptane, benzene, toluene, etc.) and mixed solvents containing two or more of the above-mentioned solvents.
  • the reaction may be completed by stirring at an appropriate temperature, for example, ⁇ 80 to ⁇ 40 ° C. for a certain period of time (for example, 0.5 to 5 hours).
  • the reaction can be post-treated by a conventional method, and the resulting product can be purified by a conventional method to give a compound of the formula (IVa), but simplification of the production process, solvent used From the viewpoint of suppression of the amount, suppression of the production cost, etc., it is preferable to carry out the following step without post-treatment of the present reaction.
  • the production method of the present invention may include the step of introducing a protecting group into the compound of formula (IVa) to obtain a compound of formula (IVb) in which P 6 is a protecting group of hydroxy group.
  • the introduction of the protective group in the step may be carried out, for example, by adding a compound of the formula (II) treated with an organometallic reagent to the compound of the formula (III), a reagent for introducing the protective group into the reaction mixture (eg, 1.0 to 2.0 equivalents) and, if necessary, an appropriate amount (for example, 0.1 to 1.0 equivalents) of a base such as triethylamine, N-methylmorpholine, ethyldiisopropylamine etc.
  • a base such as triethylamine, N-methylmorpholine, ethyldiisopropylamine etc.
  • the reaction may be completed by stirring for a certain period of time (for example, 0.1 to 5 hours).
  • silylating agents such as trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride, t-butyldiphenylsilyl chloride and the like, methyl iodide, benzyl bromide alkyl halides such as acid halide, such as pivaloyl chloride, methoxymethyl chloride, a C 1-6 alkoxy C 1-6 alkyl halide such as ethoxymethyl chloride.
  • silylating agents such as trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride, t-butyldiphenylsilyl chloride and the like, methyl iodide, benzyl bromide alkyl halides such as acid halide, such as pival
  • step b) a compound of (IVb) is used wherein P 6 is a protecting group of a hydroxy group.
  • the protective group introduction reaction can be post-treated by a conventional method, and the resulting product can be purified by a conventional method to give a compound of the formula (IVb).
  • Treatment of the compound of formula (IVb) with the organometallic reagent in step b) may be carried out using a solvent suitable for halogen transmetallation.
  • the solvent include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane and the like), hydrocarbons (for example, And pentane, hexane, heptane, benzene, toluene and the like, and mixed solvents containing two or more of the above-mentioned solvents.
  • the solvent of the previous step can be used as it is.
  • the organometallic reagent can be used in an amount of 0.3 to 4.0 equivalents, for example, 1.0 to 3.0 equivalents, preferably 1.1 to 2.1 equivalents.
  • the organometallic reagent can be added in small portions (for example, dropwise) to the system at a temperature of, for example, -100 to 30 ° C, preferably -90 to -10 ° C, especially -90 to -70 ° C. .
  • a temperature for example, -100 to 30 ° C, preferably -90 to -10 ° C, especially -90 to -70 ° C.
  • the reaction may be stirred, preferably for 0.5 to 2 hours.
  • the reaction of a compound of formula (IVb) with a compound of formula (V) treated with an organometallic reagent can be carried out, for example, by reacting a solution of the compound of formula (V) in a suitable solvent under suitable temperature, for example C., preferably -90 to -10.degree. C., in particular -80 to -70.degree. C., by adding it to the reaction mixture containing the compound of formula (IVb).
  • the compound of the formula (V) can be used in an amount of 1.0 to 15.0 equivalents, for example, 1.0 to 5.0 equivalents, preferably 1.1 to 2.2 equivalents.
  • Suitable solvents include, for example, ethers (eg, tetrahydrofuran (THF), methyl tetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane etc.), hydrocarbons And the like (eg, pentane, hexane, heptane, benzene, toluene, etc.), and mixed solvents containing two or more of the aforementioned solvents.
  • the reaction may be completed by stirring at a suitable temperature, for example, -90 to 0 ° C., for a fixed time (for example, 0.1 to 5 hours).
  • step b) can be worked up by conventional techniques and the resulting product can be purified by conventional procedures to give compounds of formula (VI). From the viewpoint of simplification of the production process, suppression of the amount of solvent used, suppression of the production cost, etc., it is preferable to carry out the next step without particularly purifying the crude product obtained by post-treatment.
  • step c) when P 1 is a protecting group for a hydroxy group, deprotection is carried out before step (1) of step c) to convert the compound into a compound wherein P 1 is a hydrogen atom .
  • said deprotection also removes the protecting groups introduced as P 2 -P 6 .
  • Deprotection can be carried out by methods known in the art, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, tri odor Acids or Lewis acids such as borohydride; bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate; organometallic reagents such as butyllithium, Grignard reagents; lithium aluminum hydride, lithium boron hydride, hydrogen Metal hydride reagents such as diisobutylaluminum halide; boron trifluoride diethyl etherate complex-ethanethiol, aluminum halide-sodium iodide, aluminum halide-thiol, aluminum halide-sulfide, etc.
  • bases such as sodium hydroxide, lithium hydroxide, potassium hydrox
  • step (1) forms a spiro ring structure.
  • the reaction of step (1) can be carried out using a suitable solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N- Methyl pyrrolidone, acetone, acetic acid ester (eg, ethyl acetate, methyl acetate, isopropyl acetate etc.), methylene chloride, chloroform, dichloroethane, water, or a mixed solvent containing two or more of the above solvents at an appropriate temperature, for example, It can be carried out at ⁇ 20 to 100 ° C., preferably 0 to 80 ° C., in particular 20 to 30 ° C.
  • a suitable solvent such as tetrahydrofuran (THF), methyltetra
  • the reaction time can be set appropriately, and is, for example, about 0.5 to 15 hours, preferably about 2 to 10 hours.
  • the acid which can be used is not particularly limited, and a Lewis acid may be used. Specific examples thereof include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, boron tribromide and the like.
  • the treatment under the acidic conditions of step (1) can simultaneously remove the protecting group introduced as P 1 to P 6 and form the spiro ring.
  • the reduction reaction in step (2) of step c) may be carried out using a suitable solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, acetic acid ester (eg, ethyl acetate, methyl acetate) (Eg, isopropyl acetate), acetone, water, or a mixed solvent containing two or more of the above-mentioned solvents under an appropriate temperature, for example, ⁇ 80 to 80 ° C., preferably ⁇ 30 to 70 ° C., particularly ⁇ 20 to 60 ° C.
  • a suitable solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, acetic acid ester (eg, ethyl acetate, methyl acetate) (Eg
  • the reaction time can be set appropriately, and is, for example, about 0.5 to 24 hours, preferably about 5 to 15 hours.
  • the reduction reaction is not particularly limited as long as it uses a suitable reducing agent and / or catalyst to remove the hydroxy group on the carbon atom linking the two benzene rings of the compound of formula (VI).
  • metal catalysts under hydrogen atmosphere eg, palladium supported on carbon, platinum, homogeneous palladium complex, homogeneous ruthenium complex, homogeneous rhodium complex
  • hydride type reducing agent combined with Lewis acid eg aluminum chloride-hydrogen
  • Lewis acid eg aluminum chloride-hydrogen
  • Sodium borohydride borohydride, trifluoroacetic acid-triethylsilane
  • the reduction reaction of step (2) can simultaneously remove the protecting group introduced to P 1 to P 6 and removing the hydroxy group. Any of steps (1) and (2) in step c) may precede, and if deprotection of P 1 or P 1 to P 6 is performed, any step prior to step (1) may be performed. Can be done with
  • the production method of the present invention may further include the step of removing any protective group contained in the compound obtained in step c), and the compound of formula (I) obtained by the production method of the present invention May be further converted to another compound of formula (I).
  • steps a) and b) can be carried out by a so-called one-pot reaction, that is, sequentially adding necessary reagents and the like without performing post-treatment or purification. Therefore, the production method of the present invention is capable of simplifying the production process, suppressing the amount of solvent used, and suppressing the production cost, etc., by performing the one-pot reaction, in addition to obtaining the desired product in a good yield. It is also very good in that it can be
  • the “hydroxy protecting group” defined as P 7 is not particularly limited as long as it is a group generally used as a hydroxy protecting group, and examples thereof include “Greene and Wuts,“ Protective Groups in Organic Synthesis ”(No. 4), John Wiley & Sons, 2006).
  • P 7 is selected from C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, -SiR 23 R 24 R 25 and R 23 , R 24 and R 25 are as defined above. As you did.
  • the protecting group introduction reaction of step d) can be carried out by methods known in the art, for example, “Greene and Wuts,” Protective Groups in Organic Synthesis “(4th edition, John Wiley & Sons 2006).
  • the solvent used in the reaction include ethers (eg, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane etc.), hydrocarbon (Eg, benzene, toluene etc.), acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetone, acetate (eg, ethyl acetate, methyl acetate, isopropyl acetate etc.), chloride
  • reagents for introducing the protective group can be selected, and examples thereof include C 1-6 alkylcarbonyl chloride, C 1-6 alkoxycarbonyl chloride, Cl-SiR 23 R 24 R 25 and the like.
  • the amount can be 1.0 to 4.0 equivalents, preferably 1.0 to 3.0 equivalents, relative to the hydroxyl group, and a base may be used as needed.
  • bases examples include triethylamine, pyridine, N, N-dimethylaniline, 4- (dimethylamino) pyridine, imidazole, 1-methylimidazole, ethyldiisopropylamine, lutidine, morpholine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. Can be mentioned. Preferably, 1-methylimidazole may be used.
  • the reaction temperature is not particularly limited, but may be, for example, -20 to 50 ° C, preferably -10 to 25 ° C, and the reaction may be stirred for a predetermined time, for example, 1 to 10 hours, preferably 2 to 4 hours. Good.
  • the crystallization in step e) may be carried out by using a suitable solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxymethane Ethane, diisopropyl ether, acetonitrile, acetone, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene or water, or a mixed solvent containing two or more of the above solvents Can be done.
  • a suitable solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl
  • recrystallization in this step may be carried out using a suitable solvent, such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxymethane Ethane, diisopropyl ether, acetonitrile, acetone, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene or water, or a mixed solvent containing two or more of the above solvents Can be carried out by methods known in the art.
  • a suitable solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, is
  • Deprotection can be carried out by selecting methods known in the art depending on the protecting group to be removed, for example, “Greene and Wuts,” Protective Groups in Organic Synthesis “(4th Edition, John Wiley & Sons 2006). Year) can be used.
  • acid or Lewis acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, boron tribromide, etc .
  • sodium hydroxide, lithium hydroxide, water Bases such as potassium oxide and potassium carbonate
  • Organometallic reagents such as butyllithium and Grignard reagents
  • Metal hydride reagents such as lithium aluminum hydride, lithium boron hydride and diisobutylaluminum hydride
  • Boron trifluoride diethyl etherate complex-ethanethiol Combination reagent of Lewis acid and nucleophile such as aluminum halide-sodium iodide, aluminum halide-thiol, aluminum halide-sulfide; carbon-supported palladium, platinum, homogeneous palladium complex, homo
  • the crude product obtained by the process comprising steps a) to c) as defined herein is used as a compound of formula (I) in step d). Since the above steps a) to c) can produce the target without purification, it is possible to combine the steps d) to f), which can perform a high degree of purification, in the efficiency of production. From the point of view of Steps d) to f) may also be combined with other methods for the preparation of compounds of formula (I).
  • high purity means that the purity is improved compared to the compound of the formula (I) used as a raw material of step d).
  • a compound of formula (I) having a purity of 90.0% by weight or more, preferably 97.0% by weight or more can be mentioned.
  • the process of the invention comprises the step of further crystallizing the compound of formula (I) of high purity obtained in step f).
  • the solvent used in the crystallization for example, water, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, 1-hexanol), ethers (eg, tetrahydrofuran, t-butyl methyl ether, Cyclopentyl methyl ether, 1,2-dimethoxyethane, diisopropyl ether), esters (eg, ethyl acetate, propyl acetate, hexyl acetate), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N -Methylpyrrolidone, N, N-dibutylformamide), halogenated hydrocarbons (eg, 1-chlorohexane), hydro
  • the compound of formula (I) obtained may be further purified by recrystallization.
  • a solvent that can be used for recrystallization for example, water, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol or 1-hexanol), ethers (eg, tetrahydrofuran, t-butyl methyl ether, cyclopentyl) Methyl ether, 1,2-dimethoxyethane or diisopropyl ether), esters (for example, ethyl acetate, propyl acetate or hexyl acetate), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or N, N-dibutylformamide), halogens (eg 1-chlorohexane), hydrocarbons (eg n-propylbenzene, he
  • highly pure compounds of formula (I) are prepared, wherein n is 0, m is 0 or 1, and R 2 is C 1-4 alkyl.
  • crystals of the compound of formula (I) of high purity are prepared, wherein n is 0, m is 0 or 1, and R 2 is C 1-4 alkyl.
  • the production method of the present invention including the above steps d) to f) is complicated in operation and requires a large amount of solvent and adsorbent, without performing purification methods such as column chromatography and the like.
  • the compound of the present invention can be produced, which is useful from the viewpoint of improving the efficiency of the production method and suppressing the production cost.
  • a method for efficiently removing impurities from a compound used as a pharmaceutical is very important, and the production method of the present invention is also useful for stably providing a safe pharmaceutical.
  • the crystals are monohydrate.
  • the monohydrate is not particularly limited as long as it is a crystal that stably holds about 1 equivalent of water under the environment (temperature, relative humidity, etc.) in which the pharmaceutical product is usually stored and used.
  • the crystals are provided as sodium acetate co-crystal or potassium acetate co-crystal.
  • a monohydrate crystal of a compound of formula (XI) of high purity is provided.
  • the sodium acetate co-crystal of the present invention has a powder X-ray diffraction pattern of 4.9 °, 14.7 °, 16.0 °, 17.1 ° and around 19.6 °, more specifically 4.9. °, 8.7 °, 9.3 °, 11.9 °, 12.9 °, 14.7 °, 16.0 °, 17.1 °, 17.7 °, 19.6 °, 21.6 And a peak at a diffraction angle (2 ⁇ ) around 22.0 °.
  • the potassium acetate co-crystal of the present invention has a powder X-ray diffraction pattern of 5.0 °, 15.1 °, 19.0 °, 20.1 ° and 25.2 °, more specifically 5.0 °.
  • Diffraction angles around 10.0 °, 10.4 °, 12.4 °, 14.5 °, 15.1 °, 19.0 °, 20.1 °, 21.4 °, and 25.2 ° It is characterized by having a peak at (2 ⁇ ).
  • the powder X-ray diffraction pattern can be measured by a conventional method.
  • the value of the diffraction angle of the powder X-ray diffraction peak of the crystal of the present invention is expected to have an error depending on the measurement conditions and the state of the sample. For example, an error of about ⁇ 0.2 is expected.
  • the monohydrate crystal of the present invention is a crystal from water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of acetone and water, and a mixed solvent of 1,2-dimethoxyethane and water Can be obtained by
  • the sodium acetate co-crystals of the present invention are, for example, methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, propyl acetate, hexyl acetate, 2-butanone, 2-heptanone, n-propylbenzene, hexylbenzene, and 1-chloro It can be obtained by crystallization from a solvent selected from hexane or a mixed solvent of two or more of the solvents, preferably from a mixed solvent of methanol and isopropanol.
  • the potassium acetate co-crystals of the present invention may be prepared, for example, from a solvent selected from methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, N, N-dibutylformamide, acetone and diisopropyl ether, or of two or more such solvents. It can be obtained from a mixed solvent, preferably from a mixed solvent of methanol and isopropanol.
  • the monohydrate crystal of the present invention has the property that the water content becomes almost constant under a certain range of relative humidity, and the handling of the compound in the preparation process is easy.
  • the monohydrate crystals, sodium acetate co-crystal and potassium acetate co-crystal of the present invention are also useful for producing a pharmaceutical preparation having good storage stability.
  • the monohydrate crystal, sodium acetate co-crystal, and potassium acetate co-crystal of the present invention can be used to efficiently and highly purify the compound of formula (XI), and a pharmaceutical comprising the compound It is also useful from the viewpoint of efficient production of
  • FIG. 1 is an example of the measurement result of the water adsorption isotherm measured in Test Example 1.
  • FIG. 2 is an example of the measurement results of powder X-ray diffraction of monohydrate crystals measured under measurement condition 1 of Test Example 5.
  • FIG. 3 is an example of the measurement results of powder X-ray diffraction of monohydrate crystals measured under measurement condition 2 of Test Example 5.
  • FIG. 4 is an example of the measurement result of powder X-ray diffraction of the amorphous body measured in Test Example 5.
  • FIG. 5 is an example of the measurement result of powder X-ray diffraction of sodium acetate co-crystal measured in Test Example 5.
  • FIG. 6 is an example of the measurement result of powder X-ray diffraction of potassium acetate co-crystal measured in Test Example 5.
  • NMR was measured using a nuclear magnetic resonance apparatus JNM-ECP-500 (manufactured by JEOL) or JNM-ECP-400 (manufactured by JEOL).
  • Mass spectrometry was measured using a mass spectrometer LCT Premier XE (manufactured by Waters).
  • Preparative high performance liquid chromatography used the GL Science preparative system.
  • Agilent 1100 manufactured by Agilent
  • the water content was measured using a KF analyzer type KF-100 (a trace water content measuring device manufactured by Mitsubishi Chemical Corporation).
  • Trimethylsilyl chloride 29.1 kg was added to a solution of D-(+)-glucono-1,5-lactone (7.88 kg) and N-methylmorpholine (35.8 kg) in tetrahydrofuran (70 kg) at 40 ° C. or less After that, the mixture was stirred at 30 to 40 ° C. for 2 hours. The solution was cooled to 0 ° C., toluene (34 kg) and water (39 kg) were added and the organic layer was separated. The organic layer was washed twice with a 5% aqueous sodium dihydrogen phosphate solution (39.56 kg) and once with water (39 kg), and the solvent was evaporated under reduced pressure to give the title compound as an oil. The product was used in step 3 below without further purification.
  • Step 2 Synthesis of 2,4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene
  • Step 3 2,3,4,5-Tetrakis (trimethylsilyloxy) -6-trimethylsilyloxymethyl-2- (5- (4-ethylphenyl) hydroxymethyl-2- (1-methoxy-1-methylethoxymethyl) Synthesis of phenyl) tetrahydropyran
  • this solution is made up of 3,4,5-tris (trimethylsilyloxy) -6-trimethylsilyloxymethyl-tetrahydropyran-2-one (Example 1, 108 g, 217 mol)
  • the solution was added dropwise to a tetrahydrofuran solution (507 ml) at -78.degree. C. and stirred at the same temperature for 2 hours.
  • Triethylamine (5.8 ml, 41 mmol) and trimethylsilyl chloride (29.6 ml, 232 mmol) are added to this solution, the temperature is raised to 0 ° C., and the mixture is stirred for 1 hour to give 2,3,4,5-tetrakis (trimethylsilyloxy)-
  • a solution containing 6-trimethylsilyloxymethyl-2- (5-bromo-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran was obtained.
  • Step 4 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) hydroxymethyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
  • the aqueous layer was further washed twice with n-heptane (693 ml), and the water was evaporated under reduced pressure to give an oil containing water and the title compound (diastereomer mixture) (187 g).
  • the product was used in the next step without further purification.
  • Step 5 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose (crude product)
  • the organic layer was washed 3 times with a 3% aqueous potassium hydrogen sulfate solution-20% aqueous sodium chloride solution, washed with a 20% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Ethanol (943 ml) was added to the obtained residue, and the mixture was heated to 75 ° C. to dissolve the residue. After cooling to 60 ° C. and adding seed crystals of the title compound, the mixture was cooled to room temperature and stirred for 1 hour. After confirming the solid precipitation, water (472 ml) was added, and the mixture was stirred at room temperature for 2 hours.
  • Step 7 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
  • the removed organic layer was washed with 25% aqueous sodium chloride solution (40 kg), and the solvent was evaporated under reduced pressure.
  • the purity of the obtained residue was calculated as the ratio of the area measured by high performance liquid chromatography to be 98.7%.
  • Acetone (32.0 kg) and water (0.8 kg) were added to the residue, and the solvent was evaporated under reduced pressure.
  • Acetone (11.7 kg) and water (15.8 kg) were added to the residue to dissolve, and the solution was cooled to 5 ° C. or less. After adding water (64 kg) to this solution at 10 ° C. or less and stirring at 10 ° C. or less for 1 hour, the obtained crystals are centrifuged and mixed with acetone (1.3 kg) and water (8.0 kg) It was washed.
  • This wet powder is dried by passing through for 8 hours under the conditions of passing temperature of 13 to 16 ° C and relative humidity of 24 to 33%, and the title compound (3.94 kg) is crystallized from monohydrate (water content: 4.502%) Got as.
  • the purity of the obtained compound was calculated as the ratio of the areas measured by high performance liquid chromatography to be 99.1%.
  • reaction mixture is subjected to workup, and the resulting residue is purified by high performance liquid chromatography (column; Inertsil ODS-3, 20 mm ID ⁇ 250 mm; acetonitrile, 30 mL / min) to give the title compound 2 Isolated as a class of diastereomers.
  • Diastereomer 5 1 H-NMR (500 MHz, CDCl 3 ) ⁇ : -0.30 (9 H, s), 0.095 (9 H, s), 0.099 (9 H, s), 0.16 (9 H, s), 0 17 (9H, s), 1.41 (3H, s), 1.43 (3H, s), 3.20 (3H, s), 3.37-3.44 (2H, m), 3.
  • Tetrahydrofuran (154 kg) was added to the residue and the solvent was evaporated under reduced pressure, and then tetrahydrofuran (154 kg) was added again and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (253 kg) to give the title compound as a tetrahydrofuran solution.
  • the purity was calculated from the area ratio measured by high performance liquid chromatography, the purity was 99.0% (conversion rate 99.1%).
  • High performance liquid chromatography measurement condition column YMC-Pack ODS-AM 4.6 mm I. D. ⁇ 150 mm, 3 ⁇ m (WEM)
  • Mobile phase A liquid: 2 mM AcONH 4 / H 2 O, B liquid: 50% (v / v) MeCN / MeOH Gradient operation: Solution B: 50% to 95% (15 minutes), 95% hold (15 minutes), 95% to 100% (5 minutes) 100% (15 minutes)
  • Flow rate 1.0 ml / min Column temperature: 40 ° C.
  • the reaction mixture was added to 20% aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with water and the solvent was evaporated under reduced pressure to give an oil containing the title compound (879 g). The product was used in the next step without further purification.
  • Step 3 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
  • the organic layer was washed with 10% aqueous potassium hydrogen sulfate-5% aqueous sodium chloride solution (800 ml). Subsequently, the organic layer was washed twice with a 20% aqueous sodium chloride solution (800 ml), and the solvent was evaporated under reduced pressure. To the resulting residue were added ethanol (1200 ml), t-butyl methyl ether (200 ml) and 2-propanol (130 ml). The mixture was heated to 74 ° C. to dissolve the residue, then cooled to 55 ° C. and stirred for 1 hour. After confirming the solid precipitation, the solution was cooled from 55 ° C. to 25 ° C. over 1.5 hours.
  • Step 5 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
  • the organic layer was washed with 18% aqueous sodium dihydrogen phosphate dihydrate-12% aqueous solution of disodium hydrogen phosphate dihydrate (410 ml), and then ethyl acetate (410 ml) was added.
  • the organic layer was washed twice with 25% aqueous sodium chloride solution (410 ml), and the solvent was evaporated under reduced pressure.
  • Acetone (410 ml) and water (8.2 ml) were added to the residue, and the solvent was evaporated under reduced pressure.
  • Acetone (164 ml) and water (655 ml) were added to the obtained residue, and the temperature was raised to 28 ° C. to dissolve the residue.
  • the mixture was cooled to 25 ° C., and after adding seed crystals (82 mg) of the title compound, it was cooled from 25 ° C. to 20 ° C. over 24 minutes and stirred at 20 ° C. for 1 hour. After confirming the solid precipitation, the temperature was raised to 25 ° C., and the mixture was stirred at 25 ° C. for 1 hour. Subsequently, it was cooled from 25 ° C. to ⁇ 5 ° C. over 2.4 hours, and the crystals were filtered. Water (246 ml) was added to the obtained crystals, and after stirring for 1 hour at 4 ° C., the crystals were filtered.
  • the resulting wet powder is dried under reduced pressure for 20 minutes (pressure: 1 hPa, outside temperature: 20-25 ° C.) to reach a moisture content of 8.249%, and subsequently dried for 30 minutes under reduced pressure ( Pressure: 25 hPa, external temperature: 20-25 ° C.) to give the title compound (44 g, yield 82%) as monohydrate crystals (water content: 4.470%).
  • the purity of the obtained compound was calculated as the ratio of the areas measured by high performance liquid chromatography to be 99.9%.
  • Example 8 Preparation of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose sodium acetate co-crystal 1,1 -Anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose monohydrate crystal (200 mg) and sodium acetate (40 mg) in methanol After dissolving in (1 ml) at 80 ° C. and cooling to room temperature, isopropanol (2 ml) was added.
  • the seed crystals used in the above preparation were obtained by the following method. Hydrate crystals of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose (8 mg) and sodium acetate (2 mg) ) was dissolved in methanol (0.1 ml) at 80 ° C. The solvent was completely evaporated from the solution at 80 ° C. to obtain the desired crystalline substance.
  • isopropanol (2 ml) was added. After distilling off the solvent (about 2 ml) under reduced pressure, seed crystals of the title co-crystal are added and stirred at room temperature overnight, and the precipitated crystals are collected by filtration, washed with isopropanol (4 ml) and dried. The title co-crystal (melting point about 176 ° C.) was obtained.
  • the seed crystals used in the above preparation were obtained by the following method. Hydrate crystal of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose (8 mg) and potassium acetate (2 mg) ) was dissolved in methanol (0.1 ml) at 80 ° C. The solvent was completely evaporated from the solution at 80 ° C. to obtain the desired crystalline substance. The melting point was measured in the same manner as in Example 7. [Test Example 1] Measurement of water adsorption isotherm of monohydrate crystal Formula (XI):
  • the water adsorption isotherm was measured as follows using a dynamic water adsorption isotherm: DVS-1 (Surface Measurement Systems) for monohydrate crystals of the compound of
  • the monohydrate crystal (about 10 mg, water content 4.5%) of the said compound ground on a sample pan was accurately weighed and used as a measurement sample.
  • An empty sample pan served as a control sample.
  • Set the measurement sample and control sample in the device 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, and 0% at a constant temperature around 25 ° C
  • the relative humidity (RH) was changed in order, and the mass change of the measurement sample was measured.
  • the measurement results are shown in FIG. It has been found that the compounds of the formula (XI) are stably present in the monohydrate in the range of 10-90% relative humidity.
  • Test Example 2 Storage stability test of monohydrate crystal The storage stability test was conducted using the monohydrate crystal of the compound of the formula (XI) of the present invention and the amorphous of the compound.
  • the monohydrate crystal of the compound of formula (XI) was produced according to the method described in step 7 of Example 1.
  • the amorphous of the compound of formula (XI) was prepared by the following method. Monohydrated crystal (15 g) of the compound is heated on a hot stage, and after melting, it is allowed to cool at room temperature in a humidity controller (25 ° C./dry), and solidified by grinding in a mortar. The sample was used as a sample. Each sample was stored in a thermostat set at 25 ° C. and 40 ° C., and the purity of the sample was confirmed after one month, three months and six months.
  • the purity was confirmed by the following procedure.
  • the sample (about 6 mg) was weighed, dissolved in a water / methanol mixture (1: 1) to make exactly 10 mL, and used as a sample solution.
  • Each prepared solution (10 ⁇ L) was subjected to HPLC analysis under the following conditions, and the total amount of impurities was calculated according to the following equation.
  • Test Example 3 Storage Stability Test of Sodium Acetate Co-Crystal Using the sodium acetate co-crystal of the compound of the formula (XI) of the present invention, a storage stability test was conducted according to the method of Test Example 2. Sodium acetate co-crystal of the compound of formula (XI) was prepared according to the method described in Example 5. The samples were stored in thermostatic baths set at 25 ° C. and 40 ° C., and the purity of the samples was confirmed after 1 and 3 months. The obtained measurement results were compared with the amorphous results obtained in Test Example 2.
  • Test Example 4 Storage Stability Test of Potassium Acetate Co-Crystal Using the potassium acetate co-crystal of the compound of the formula (XI) of the present invention, a storage stability test was conducted according to the method of Test Example 2. Potassium acetate co-crystal of the compound of formula (XI) was prepared according to the method described in Example 6. The samples were stored in thermostatic baths set at 25 ° C. and 40 ° C., and the purity of the samples was confirmed after 1 and 3 months. The obtained measurement results were compared with the amorphous results obtained in Test Example 2.
  • Test Example 5 Powder X-Ray Diffraction Measurement Powder X-ray diffraction of a monohydrate crystal, amorphous, sodium acetate co-crystal and potassium acetate co-crystal of the compound of formula (XI) was measured. The measurement conditions are shown below.
  • Measurement condition of monohydrate crystal (measurement condition 1) Measuring device: RINT1100 (manufactured by Rigaku) Anticathode: Cu Tube voltage: 40kV Tube current: 40 mA Scanning speed: 2.000 ° / min Sampling width: 0.020 ° Divergence slit: 1 ° Scattering slit: 1 ° Light receiving slit: 0.15 mm Scanning range: 3 to 35 ° Measurement condition of monohydrate crystal (measurement condition 2) Measuring device: X'Pert-Pro MPD (manufactured by PANalytical) Anticathode: Cu Tube voltage: 45kV Tube current: 40 mA Scanning method: Continuous Step width: 0.017 Scanning axis: 2 ⁇ Sampling time per step: 30 seconds Scanning range: 2 to 35 ° Measurement condition measuring device for amorphous : RINT 1100 (manufactured by Rigaku) Anticathode: Cu Tube voltage: 40k

Abstract

L'invention porte sur un procédé de fabrication d'un dérivé de spirocétal par l'intermédiaire d'un composé représenté par la formule (VI) [dans laquelle les groupes variables et les nombres variables sont tels que définis dans la description] qui peut être obtenu à partir d'un dérivé d'alcool dihalobenzylique par une réaction monotope.
PCT/JP2009/061226 2008-06-20 2009-06-19 Cristaux de dérivé de spirocétal et leur procédé de fabrication WO2009154276A1 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
MX2010014023A MX2010014023A (es) 2008-06-20 2009-06-19 Cristal de derivados de espirocetal, y procedimiento para la preparacion de derivados de espirocetal.
EP09766724.0A EP2308886B1 (fr) 2008-06-20 2009-06-19 Procédé de fabrication d'un dérivé de spirocétal
EP16202285.9A EP3170834B8 (fr) 2008-06-20 2009-06-19 Formes cristallines de 2'-[2h]pyran]-3',4',5'-triol de (1s,3'r,4's,5's,6'r)-6-[(4-ethylphenyl)methyl]-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro[isobenzofuran-1(3h)
EP22155547.7A EP4036100A1 (fr) 2008-06-20 2009-06-19 Dérivés de spirocétals et procédé de production de dérivés de spirocétals
CN200980119081.4A CN102046645B (zh) 2008-06-20 2009-06-19 螺酮缩醇衍生物的结晶及其制备方法
PL16202285T PL3170834T3 (pl) 2008-06-20 2009-06-19 Krystaliczne postacie (1s,3’r,4’s,5’s,6’r)-6-[(4-etylofenylo)metylo]-3’,4’,5’,6’-tetrahydro-6’-(hydroksymetylo)spiro[izobenzofurano-1(3h) 2’-[2h]pirano]-3’,4’,5’-triolu
JP2010517979A JP4823385B2 (ja) 2008-06-20 2009-06-19 スピロケタール誘導体の結晶およびその製造方法
NZ589961A NZ589961A (en) 2008-06-20 2009-06-19 Crystal of spiroketal derivative, and process for production thereof
CA2727923A CA2727923A1 (fr) 2008-06-20 2009-06-19 Cristaux de derive de spirocetal et leur procede de fabrication
US13/000,208 US8569520B2 (en) 2008-06-20 2009-06-19 Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives
KR1020117000778A KR101856784B1 (ko) 2008-06-20 2009-06-19 스피로케탈 유도체의 결정 및 그 제조 방법
AU2009261129A AU2009261129A1 (en) 2008-06-20 2009-06-19 Crystal of spiroketal derivative, and process for production thereof
IL210098A IL210098A0 (en) 2008-06-20 2010-12-19 Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives
MA33442A MA32530B1 (fr) 2008-06-20 2010-12-20 Dérivés de spirocétals cristallins et procédé pour la préparation de dérivés de spirocétals
ZA2011/00016A ZA201100016B (en) 2008-06-20 2011-01-03 "crystal of spiroketal derivatives and process for preparation of spiroketal derivatives"
HK11108698.5A HK1154589A1 (en) 2008-06-20 2011-08-17 Crystal of spiroketal derivative, and process for production thereof
US14/034,880 US9163051B2 (en) 2008-06-20 2013-09-24 Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives

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WO2011074675A1 (fr) * 2009-12-18 2011-06-23 中外製薬株式会社 Procédé de préparation d'un dérivé spirocétal
WO2012115249A1 (fr) * 2011-02-25 2012-08-30 中外製薬株式会社 Cristal de dérivé de spirocétal
WO2015099139A1 (fr) 2013-12-27 2015-07-02 中外製薬株式会社 Préparation solide comprenant de la tofogliflozine et procédé de production associé
WO2018073154A1 (fr) 2016-10-19 2018-04-26 Boehringer Ingelheim International Gmbh Combinaisons comprenant un inhibiteur de ssao/vap-1 et un inhibiteur de sglt2, leurs utilisations
WO2019201752A1 (fr) 2018-04-17 2019-10-24 Boehringer Ingelheim International Gmbh Composition pharmaceutique, méthodes de traitement et utilisations associées

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AU2012320581B2 (en) * 2011-10-06 2017-03-30 Bayer Intellectual Property Gmbh Heterocyclylpyri (mi) dinylpyrazole as fungicidals
CN106188190B (zh) * 2016-07-28 2020-08-25 迪嘉药业集团有限公司 一种托格列净一水合物的制备方法
CN108640958B (zh) * 2017-05-05 2021-03-30 镇江圣安医药有限公司 异苯并呋喃衍生物、其药物组合物和制剂以及用途

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WO2011074675A1 (fr) * 2009-12-18 2011-06-23 中外製薬株式会社 Procédé de préparation d'un dérivé spirocétal
WO2012115249A1 (fr) * 2011-02-25 2012-08-30 中外製薬株式会社 Cristal de dérivé de spirocétal
JPWO2012115249A1 (ja) * 2011-02-25 2014-07-07 中外製薬株式会社 スピロケタール誘導体の結晶
US10398653B2 (en) 2013-12-27 2019-09-03 Chugai Seiyaku Kabushiki Kaisha Solid preparations containing tofogliflozin and process of producing the same
KR20160101719A (ko) 2013-12-27 2016-08-25 추가이 세이야쿠 가부시키가이샤 토포글리플로진을 함유하는 고형 제제 및 그 제조 방법
JPWO2015099139A1 (ja) * 2013-12-27 2017-03-23 中外製薬株式会社 トホグリフロジンを含有する固形製剤及びその製造方法
US10231930B2 (en) 2013-12-27 2019-03-19 Chugai Seiyaku Kabushiki Kaisha Solid preparations containing tofogliflozin and process of producing the same
EP3482748A1 (fr) 2013-12-27 2019-05-15 Chugai Seiyaku Kabushiki Kaisha Préparations solides comprenant de la tofogliflozine et procédé de production associé
WO2015099139A1 (fr) 2013-12-27 2015-07-02 中外製薬株式会社 Préparation solide comprenant de la tofogliflozine et procédé de production associé
RU2700164C2 (ru) * 2013-12-27 2019-09-13 Чугаи Сейяку Кабусики Кайся Твердые препараты, содержащие тофоглифлозин, и способ их получения
JP2020203918A (ja) * 2013-12-27 2020-12-24 中外製薬株式会社 トホグリフロジンを含有する固形製剤及びその製造方法
KR20210082557A (ko) 2013-12-27 2021-07-05 추가이 세이야쿠 가부시키가이샤 토포글리플로진을 함유하는 고형 제제 및 그 제조 방법
WO2018073154A1 (fr) 2016-10-19 2018-04-26 Boehringer Ingelheim International Gmbh Combinaisons comprenant un inhibiteur de ssao/vap-1 et un inhibiteur de sglt2, leurs utilisations
WO2019201752A1 (fr) 2018-04-17 2019-10-24 Boehringer Ingelheim International Gmbh Composition pharmaceutique, méthodes de traitement et utilisations associées

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